Antagonists of vascular endothelial growth factor (VEGF) have been shown to effectively inhibit tumor growth in numerous experimental and clinical settings. VEGF antagonists exert their therapeutic effects by targeting the tumor vasculature. It has been observed, however, that tumors under certain circumstances can develop resistance to anti-VEGF agents. Thus, there is a need in the art for new therapeutic approaches for treating tumors, including methods of inhibiting the growth of tumors that have developed resistance to anti-VEGF therapies.
Interleukin-6 (“IL-6”) is a pro-inflammatory cytokine that is expressed in multiple cancer types. Clinical studies have shown that increased serum IL-6 levels are associated with worse patient outcomes. Elevated expression of IL-6 can result from the activation of oncogenic signaling pathways and/or as a consequence of chronic inflammation, which has been associated with the development of cancer. IL-6 signals through its heterodimeric receptor IL-6R/gp130 to activate the JAK/STAT and Ras signaling pathways. In particular, IL-6 strongly activates STAT3, which has been shown to promote tumor cell proliferation, invasion and survival. Inhibition of IL-6 signaling with monoclonal antibodies directed against IL-6 or IL-6R has been shown to inhibit tumor growth in several preclinical models, suggesting that the IL-6 pathway is an attractive therapeutic target for cancer. An association between IL-6 levels and anti-VEGF resistance, or the use of IL-6 antagonists to treat anti-VEGF resistant tumors, however, has not been described.